Delta-9-Tetrahydrocannabinol (THC), the active ingredient in the cannabis plant, has a wide range of pharmacological properties of therapeutic value. The drug has been approved by the Food and Drug Administration (FDA) (Marinol(r) soft gelatin capsules) for the treatment of nausea and vomiting associated with chemotherapy and for appetite stimulation in AIDS patients suffering from the wasting syndrome. Other therapeutic possibilities include pain management (chronic pain), glaucoma (lowering the intraocular pressure), and anxiety. The only formulation available in the United States is the soft gelatin oral capsule. This formulation suffers from several shortcomings including low and erratic bioavailability and first pass effect which results in relatively high levels of 11-OH-THC, a metabolite with much more prominent psychological properties which contribute to the side effects of the drug. In addition, multiple daily doses are required for therapeutic efficacy. The increased interest in THC (and other cannabinoids) therapeutic activities necessitated the search for alternative delivery systems, as was recommended in the Institute of Medicine (IOM) Report of 1999. We have, therefore, embarked on the development of a new formulation based on Hot Melt Extension (HME) to deliver THC from a Transmucosal Matrix Patch (TMP). During the Phase I period, and in efforts carried out thereafter (in preparation for this application), several formulations were prepared and tested that contained THC or a prodrug thereof. Although in vitro studies exhibited encouraging stability, bioadhesive, and permeation results for THC from TMP, bioavailability in the rabbit animal model was not observed. A prodrug of THC, THC-hemisuccinate (or THC-HS), was investigated, and a formulation for incorporation into a TMP system was developed with positive stability, bioadhesive, and permeability profile. In vivo testing of the THC-HS formulation in the rabbit model demonstrated extremely promising results, where blood levels reached up to 6 ng/mL THC and 17 ng/mL of THC acid metabolite, with almost no 11-OH-THC, showing a true transmucosal absorption of the drug and bypassing of the first pass. The goal of this Phase II application is to capitalize on the results obtained during Phase I, and to develop a formulation for the effective, sustained delivery of THC from a TMP system incorporating the most suitable THC prodrug. Therefore, different prodrugs will be synthesized during Phase II and evaluated for the selection of the best prodrug/formulation(s) based on stability, bioadhesive, and permeation in vitro profiles. In vivo evaluation will include LD50 determinations for each prodrug, with only those having LD50 comparable to or higher than that of THC qualifying for further studies. Promising formulations will then be evaluated in vivo, first in the rabbit model and then in the pig model (more predictive of systemic absorption in humans). Finally, the selected prodrug will be cGMP produced, and stability data (at least three months) will be generated to support the use of the API in preparing TMP systems supply for Phase I clinical evaluation. Narrative: This Phase II application is directed toward the development of a Transmucosal Patch (TMP) System for the effective and sustained delivery of THC. Such delivery system will be of great value for patients suffering from conditions for which THC would be an effective drug (nausea and vomiting in cancer patients, appetite stimulation in AIDS patients, treatment of chronic pain, glaucoma, and anxiety).